US20170368037A1 - Pharmaceutical composition for promotion of fibrinolysis - Google Patents

Pharmaceutical composition for promotion of fibrinolysis Download PDF

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Publication number
US20170368037A1
US20170368037A1 US15/538,676 US201515538676A US2017368037A1 US 20170368037 A1 US20170368037 A1 US 20170368037A1 US 201515538676 A US201515538676 A US 201515538676A US 2017368037 A1 US2017368037 A1 US 2017368037A1
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Prior art keywords
edoxaban
pci
imidazol
fibrinolysis
salt
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Abandoned
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US15/538,676
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English (en)
Inventor
Taketoshi Furugori
Yoshiyuki Morishima
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Daiichi Sankyo Co Ltd
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Daiichi Sankyo Co Ltd
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Assigned to DAIICHI SANKYO COMPANY, LIMITED reassignment DAIICHI SANKYO COMPANY, LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MORISHIMA, YOSHIYUKI, FURUGORI, Taketoshi
Publication of US20170368037A1 publication Critical patent/US20170368037A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a pharmaceutical composition for the promotion of fibrinolysis, comprising edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the salt, a method for promoting fibrinolysis using edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the salt, and combined use or a combination drug of edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the salt with an agent having a TAFIa inhibitor for the promotion of fibrinolysis.
  • Edoxaban tosylate hydrate competitively and selectively inhibits activated blood coagulation factor X (hereinafter, referred to as “FXa”) in mammals such as humans.
  • FXa activated blood coagulation factor X
  • compositions containing edoxaban tosylate hydrate have indications and usage, such as reduction in the risks of stroke and systemic embolism in non-valvular atrial fibrillation patients, and treatment of deep vein thrombosis and pulmonary embolism (see e.g., Non-Patent Literatures 1 and 2).
  • Urokinase, streptokinase, tPA, and the like are used for lysing thrombus (see e.g., Non-Patent Literature 3).
  • An object of the present invention is to provide a method for promoting fibrinolysis using an FXa inhibitor such as edoxaban or using an FXa inhibitor such as edoxaban and a TAFIa inhibitor.
  • the present invention provides:
  • the present invention exerts an effect in that a novel pharmaceutical composition that can promote fibrinolysis can be provided.
  • FIG. 1 is a diagram showing the influence of edoxaban on fibrinolytic phenomenon induced by tPA in human plasma.
  • FIG. 2 is a diagram showing the influence of edoxaban on clot lysis time induced by tPA in human plasma.
  • significant difference from control by Dunnett's multiple comparison test is indicated by * (P ⁇ 0.05) and *** (P ⁇ 0.001).
  • FIG. 3 is a diagram showing the influence of edoxaban ( FIG. 3A ) or PCI ( FIG. 3B ) on fibrinolytic phenomenon induced by tPA in human plasma.
  • FIG. 4 is a diagram showing the influence of edoxaban ( FIG. 4B ) or PCI ( FIG. 4A ) on clot lysis time induced by tPA in human plasma.
  • significant difference from control by paired t-test with Bonferroni correction is indicated by *** (P ⁇ 0.001).
  • the control refers to a group involving neither PCI nor edoxaban.
  • FIG. 5 is a diagram showing the influence of edoxaban, PCI, and combinations thereof on fibrinolytic phenomenon induced by tPA in human plasma.
  • FIG. 5A shows the influence of PCI
  • FIG. 5B shows the influence of edoxaban
  • FIG. 5C shows the influence of the combined use of 150 ng/mL edoxaban and PCI
  • FIG. 5D shows the influence of the combined use of 300 ng/mL edoxaban and PCI.
  • FIG. 6 is a diagram showing the influence of edoxaban, PCI, and combinations thereof on clot lysis time induced by tPA in human plasma.
  • significant difference from control by paired t-test with Bonferroni correction is indicated by ### (P ⁇ 0.001).
  • the control refers to a group involving neither PCI nor edoxaban.
  • significant difference from 75, 150, or 300 ng/mL edoxaban by paired t-test with Bonferroni correction is indicated by (P ⁇ 0.05), ** (P ⁇ 0.01), and *** (P ⁇ 0.001).
  • fibrinolysis refers to lysis of thrombus.
  • edoxaban means N-(5-chloropyridin-2-yl)-N′-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl]oxamide represented by the following formula:
  • salts of edoxaban include hydrochloride, sulfate, hydrobromide, citrate, hydroiodide, phosphate, nitrate, benzoate, methanesulfonate, benzenesulfonate, 2-hydroxyethanesulfonate, tosylate, acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, fumarate, malate and mandelate.
  • the salt of edoxaban is preferably hydrochloride, tartrate or tosylate, more preferably tosylate.
  • edoxaban or the pharmaceutically acceptable salt thereof, or the hydrate of the compound or the salt is preferably edoxaban tosylate hydrate represented by the following formula:
  • a commercially available product can be used as the edoxaban or the pharmaceutically acceptable salt thereof, or the hydrate of the compound or the salt.
  • TAFI refers to a thrombin-activatable fibrinolysis inhibitor.
  • TAFIa refers to activated TAFI.
  • TAFIa inhibitor refers to an agent inhibiting TAFIa.
  • Examples of the TAFIa inhibitor used in the present invention include a carboxypeptidase inhibitor from potato tuber (hereinafter, also referred to as “PCI”), 5-amino-2-[(1-cyclohexyl-1H-imidazol-4-yl)methyl]valeric acid, 5-amino-2-[[1-(4-methylcyclohexyl)-1H-imidazol-4-yl]methyl]valeric acid, 5-amino-2-[[1-(4-ethylcyclohexyl)-1H-imidazol-4-yl]methyl]valeric acid, 5-amino-2-[[1-(3-ethylcyclobutyl)-1H-imidazol-4-yl]methyl]valeric acid, 5-amino-2- ⁇ [1-(3-methylcyclobutyl)-1H-imidazol-4-yl]methyl ⁇ valeric acid, 5-amino-2-([1-[(1
  • the phrase “comprising edoxaban or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the salt in combination with an agent having a TAFIa inhibitor” refers to a form in which a preparation containing the edoxaban or the pharmaceutically acceptable salt thereof, or the hydrate of the compound or the salt is administered at the same time with or separately from a preparation containing the TAFIa inhibitor, or a form in which a preparation containing both of the edoxaban or the pharmaceutically acceptable salt thereof and the TAFIa inhibitor (hereinafter, referred to as a “combination drug”) is administered.
  • administration “at the same time” refers to administration at substantially the same time.
  • TAFIa inhibitor is first administered, and subsequently, the edoxaban or the pharmaceutically acceptable salt thereof, or the hydrate of the compound or the salt is administered after elapse of a predetermined time, or vice versa.
  • the administration can be systemic or local and oral or parenteral.
  • the pharmaceutical composition or the combination drug of the present invention can be prepared according to various formulation methods usually used by selecting an appropriate form according to the administration method.
  • oral dosage forms of the pharmaceutical composition or the combination drug include tablets, powders, granules, capsules, suspensions, emulsions, syrups and elixirs.
  • the pharmaceutical composition in such a form can be produced according to a routine method by selecting an additive usually used such as an excipient, a binder, a disintegrant, a lubricant, a swelling agent, a swelling aid, a coating agent, a plasticizer, a stabilizer, an antiseptic, an antioxidant, a colorant, a solubilizer, a suspending agent, an emulsifier, a sweetener, a preservative, a buffer, a diluent or a wetting agent according to need.
  • an additive usually used such as an excipient, a binder, a disintegrant, a lubricant, a swelling agent, a swelling aid, a coating agent, a plasticizer, a stabilizer, an antiseptic, an antioxidant, a colorant
  • parenteral dosage forms of the pharmaceutical composition or the combination drug include injections, ointments, gels, creams, poultices, patches, aerosolized agents, inhalants, sprays, eye drops, nasal drops and suppositories.
  • the pharmaceutical composition in such a form can be produced according to a routine method by selecting an additive usually used such as a stabilizer, an antiseptic, a solubilizer, a humectant, a preservative, an antioxidant, a flavor, a gelling agent, a neutralizing agent, a buffer, a tonicity agent, a surfactant, a colorant, a buffering agent, a thickener, a wetting agent, a filler, an absorption promoter, a suspending agent or a binder according to need.
  • an additive usually used such as a stabilizer, an antiseptic, a solubilizer, a humectant, a preservative, an antioxidant, a flavor, a gelling agent, a neutralizing agent, a buffer, a tonicity agent, a surfactant, a colorant, a buffering agent, a thickener, a wetting agent, a filler, an absorption promoter, a suspending agent
  • the dose of the edoxaban or the pharmaceutically acceptable salt thereof, or the hydrate of the compound or the salt contained in the pharmaceutical composition of the present invention differs depending on symptoms, age, body mass, etc.
  • the edoxaban or the pharmaceutically acceptable salt thereof, or the hydrate of the compound or the salt is administered once to several times a day at a dose of 1 to 200 mg, preferably 5 to 100 mg, more preferably 15 to 60 mg, in terms of the amount of edoxaban per dose in an adult.
  • a TAFIa inhibitor an appropriate decrease in its dose is also taken into consideration in light of the risk of bleeding.
  • the pharmaceutical composition or the combination drug thus obtained can be used for promoting fibrinolysis.
  • the pharmaceutical composition or the combination drug can be used for, for example, the suppression of occurrence of venous thromboembolism (deep venous thrombosis and pulmonary thromboembolism), the treatment and the suppression of recurrence of venous thromboembolism, the suppression of occurrence of ischemic stroke and systemic embolism in non-valvular atrial fibrillation patients, the suppression of occurrence of postthrombotic syndrome, the suppression of occurrence of chronic thromboembolic pulmonary hypertension, the lysis of arterial thrombus in ischemic cerebral infarction and acute coronary syndrome, the suppression of recurrence of ischemic cerebral infarction and acute coronary syndrome, and the treatment and the suppression of recurrence of peripheral arterial disease.
  • Edoxaban was dissolved in dimethyl sulfoxide (hereinafter, also referred to as “DMSO”) (Wako Pure Chemical Industries, Ltd.) to prepare a 10 mM solution, which was then stored at ⁇ 30° C. Before use, the frozen product was thawed and diluted with DMSO and saline (Otsuka Pharmaceutical Factory, Inc.) (DMSO concentration in test substance solution: 0.96%, final DMSO concentration in reaction system: 0.08%).
  • DMSO dimethyl sulfoxide
  • Hepes buffer Hepes (Sigma-Aldrich, Co. LLC.) and NaCl (Nacalai Tesque Inc.) were dissolved at 20 mM and 140 mM, respectively, in distilled water, and the solution was adjusted to pH 7.4 using a 1 mol/L sodium hydroxide solution (Nacalai Tesque Inc.). The buffer was stored at 4° C., and BSA (final concentration: 0.01%) (Sigma-Aldrich, Co. LLC.) was added thereto in use.
  • tPA ACTIVACIN for Injection 6 million, Kyowa Hakko Kirin Co., Ltd.
  • the solution was prepared at 1.034 mg/mL (600,000 U/mL) with injectable water included in the product, and stored at ⁇ 80° C. Before use, the frozen product was thawed and diluted with Hepes buffer for use.
  • the time for the absorbance to return to 1 ⁇ 2 of the peak from the time to reach 1 ⁇ 2 of the peak was calculated using SoftMax Pro 5.4.1 (Molecular Devices, LLC.) and used as clot lysis time.
  • SoftMax Pro 5.4.1 Molecular Devices, LLC.
  • a group using a 0.96% DMSO solution instead of edoxaban was used as control group.
  • Edoxaban was dissolved in DMSO to prepare a 10 mM solution, which was then stored at ⁇ 30° C. Before use, the frozen product was thawed and diluted with DMSO and saline (DMSO concentration in test substance solution: 1.92%).
  • PCI Sigma-Aldrich, Co. LLC.
  • Hepes buffer, tPA solution, and PPP reagent were prepared in the same way as in Example 1(2).
  • Thrombomodulin (hereinafter, also referred to as “TM”) (Recomodulin for Intravenous Injection 12800, Asahi Kasei Pharma Corporation) was adjusted to 15.6 ⁇ M (1 mg/mL) with saline and stored at ⁇ 30° C. Before use, the frozen product was thawed and diluted with saline for use.
  • the time for the absorbance to decrease to 1 ⁇ 2 of the peak from the time to reach 1 ⁇ 2 of the peak was calculated using SoftMax Pro 5.4.1 and used as clot lysis time.
  • a group using a 1.92% DMSO solution and saline instead of edoxaban and PCI was used as control group.
  • the adjusted P value was calculated by multiplication by “3” (the number of repeats of the test). *The control group and the edoxaban-alone group were compared by the paired t-test (Bonferroni correction). The adjusted P value was calculated by multiplication by “2” (the number of repeats of the test).
  • the adjusted P value was calculated by multiplication by “2” (the number of repeats of the test). #The control group and the edoxaban-alone group or the PCI-alone group were compared by the paired t-test (Bonferroni correction). The adjusted P value was calculated by multiplication by “3” (the number of repeats of the test).

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US15/538,676 2014-12-26 2015-12-25 Pharmaceutical composition for promotion of fibrinolysis Abandoned US20170368037A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2014263765 2014-12-26
JP2014-263765 2014-12-26
PCT/JP2015/086178 WO2016104678A1 (ja) 2014-12-26 2015-12-25 線溶を促進するための医薬組成物

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US (1) US20170368037A1 (de)
EP (1) EP3238721A4 (de)
JP (1) JPWO2016104678A1 (de)
TW (1) TW201628617A (de)
WO (1) WO2016104678A1 (de)

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JP4085190B2 (ja) * 2001-04-24 2008-05-14 秀親 岡田 カルボキシペプチダーゼｒの活性を抑制する低分子ペプチド
MY149356A (en) * 2007-03-29 2013-08-30 Daiichi Sankyo Co Ltd Pharmaceutical composition
DK2548871T3 (da) * 2010-03-18 2017-11-06 Daiichi Sankyo Co Ltd Cycloalkylsubstitueret imidazolderivat
JP5778133B2 (ja) * 2010-03-18 2015-09-16 第一三共株式会社 シクロプロパンカルボン酸誘導体
ES2560955T3 (es) * 2010-03-19 2016-02-23 Daiichi Sankyo Company, Limited Cristal de derivado de diamina y procedimiento de producción del mismo
WO2013039202A1 (ja) * 2011-09-15 2013-03-21 第一三共株式会社 新規アクリル酸誘導体
US20130158069A1 (en) * 2011-12-14 2013-06-20 Daiichi Sankyo Company, Limited Preventive and/or therapeutic agent for thromboembolism in thromboembolism patient with severe renal impairment

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EP3238721A1 (de) 2017-11-01
TW201628617A (zh) 2016-08-16
JPWO2016104678A1 (ja) 2017-10-12
WO2016104678A1 (ja) 2016-06-30

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